The microtubule cytoskeleton provides a structural framework for the transport and positioning of membrane organelles and macromolecules, and is essential for cell division, cell motility and cell signaling. Disruption of microtubule-dependent transport underlies the pathogenesis and progression of cancer and neurodegeneration. Understanding the molecular mechanisms that control MT-dependent motility and MT organization is of paramount significance for the development of MT-based therapeutic interventions, many of which are being clinically applied. Recently, we discovered that a novel family of GTPases termed septins is essential for the microtubule-dependent transport of chromosomes and membrane vesicles. Septins are linked to a diversity of cancers and neurodegenerative diseases including Alzheimer's and Parkinson's. The long-term goal of our research is to understand how septins function in microtubule-dependent motility. We hypothesize that septins selectively modulate the interaction of microtubules with motors and microtubule-associated proteins (MAPs). Here, we will determine the molecular mechanism by which septins interact with microtubules. Importantly, we will test how septins influence the microtubule binding of specific motors and MAPs. We will use this knowledge to elucidate septin roles in the directionality and/or velocity of membrane traffic in live epithelia and neurons. Because the directionality of intracellular transport is influenced by the stability and orientation of individual microtubule tracks, we will examine how septins control the spatial organization and stability of microtubules. Our studies will provide new insights into the regulation of microtubule-dependent transport, and generate a model for the design of septin-based therapeutics (e.g., inhibitory peptides), which can be used as an alternative to microtubule-targeting agents.